2-取代硫代-N-(4-取代噻唑/1H-咪唑-2-基)乙酰胺类作为 BACE1 抑制剂的合成、生物评价及对接研究。
2-Substituted-thio-N-(4-substituted-thiazol/1H-imidazol-2-yl)acetamides as BACE1 inhibitors: Synthesis, biological evaluation and docking studies.
机构信息
Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China.
Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China.
出版信息
Eur J Med Chem. 2017 Sep 8;137:462-475. doi: 10.1016/j.ejmech.2017.06.020. Epub 2017 Jun 10.
In this work, a series of 2-substituted-thio-N-(4-substituted-thiazol/1H-imidazol-2-yl)acetamide derivatives were developed as β-secretase (BACE-1) inhibitors. Supported by docking study, a small library of derivatives were designed, synthesized and biologically evaluated in vitro. In addition, the selected compounds were tested with affinity (K) towards BACE-1, blood brain barrier (BBB) permeability and cytotoxicity. The studies revealed that the most potent analog 41 (IC = 4.6 μM) with high predicted BBB permeability and low cellular cytotoxicity, could serve as a good lead structure for further optimization.
在这项工作中，我们开发了一系列 2-取代硫代-N-(4-取代噻唑/1H-咪唑-2-基)乙酰胺衍生物，作为β-分泌酶（BACE-1）抑制剂。在对接研究的支持下，我们设计、合成并在体外对一个小型衍生物文库进行了生物评估。此外，我们还测试了所选化合物与 BACE-1 的亲和力（K）、血脑屏障（BBB）通透性和细胞毒性。研究表明，最有效的类似物 41（IC=4.6 μM）具有较高的预测 BBB 通透性和较低的细胞毒性，可作为进一步优化的良好先导结构。
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